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Characterization of transforming growth factor-beta-resistant subclones isolated from a transforming growth
K M Mulder1, M K Ramey, N M Hoosein
1Bristol-Baylor Laboratory, Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.
Abstract:
Previous work indicated that transforming growth factor-beta (TGF-beta) elicits proliferation-inhibitory effects in the human colon carcinoma cell line MOSER. This paper describes the isolation and characterization of spontaneously arising subclones from this TGF-beta-sensitive parental line which were relatively refractory to the inhibitory effects of TGF-beta. While the parental cell line responded to TGF-beta with an inhibition of cellular proliferation in monolayer culture and in soft agarose, an increase in extracellular fibronectin, and a down-regulation of c-myc protooncogene expression, these responses were absent or attenuated in the sublines. However, the resistant clones retained the ability to specifically bind TGF-beta. N,N-Dimethylformamide and retinoic acid, two other agents associated with induction of a partial differentiation-like response in the MOSER parental cells (similar to that elicited by TGF-beta), inhibited the monolayer proliferation of both the parental cells and the TGF-beta-resistant sublines. Thus, the refractoriness observed in the isolated clones was relatively specific for TGF-beta.
Insights
Researchers identified colon cancer cell subclones resistant to transforming growth factor-beta (TGF-beta). These cells, while still binding TGF-beta, lost its typical inhibitory effects on proliferation and gene expression, indicating specific resistance mechanisms.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- Transforming growth factor-beta (TGF-beta) is known to inhibit proliferation in MOSER human colon carcinoma cells.
- Understanding resistance mechanisms to TGF-beta is crucial for cancer therapy.
Purpose of the Study:
- To isolate and characterize spontaneously arising subclones of MOSER cells that are refractory to TGF-beta's inhibitory effects.
- To investigate the specificity of this refractoriness.
Main Methods:
- Isolation and characterization of TGF-beta-resistant MOSER cell subclones.
- Assessing cellular proliferation in monolayer and soft agarose cultures.
- Measuring extracellular fibronectin and c-myc protooncogene expression.
- Evaluating TGF-beta binding affinity.
- Testing responses to N,N-Dimethylformamide and retinoic acid.
Main Results:
- Isolated subclones exhibited refractoriness to TGF-beta's inhibitory effects on proliferation.
- These resistant subclones maintained the ability to bind TGF-beta.
- TGF-beta-induced increases in fibronectin and decreases in c-myc expression were attenuated in resistant subclones.
- Refractoriness was specific to TGF-beta, as other agents like N,N-Dimethylformamide and retinoic acid still inhibited proliferation.
Conclusions:
- Spontaneously arising resistance to TGF-beta in MOSER colon carcinoma cells can occur.
- This resistance is specific for TGF-beta and does not affect responses to other differentiation-inducing agents.
- The findings highlight the complexity of TGF-beta signaling pathways and potential mechanisms of therapeutic resistance in colon cancer.